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Update on Fuzeon and T-1249 Fusion Inhibitor Halted Development
  written by Jules Levin, NATAP
In the news yesterday, Roche and Trimeris announced a halt to current human clinical studies for their next generation fusion inhibitor, T-1249, the next generation T-20. Studies in patients showed T-1249 to be more potent than Fuzeon and effective against Fuzeon resistance. Thus T-1249 was expected to be the next generation Fusion inhibitor and to be effective for patients with resistance to Fuzeon.
A first reaction to the news that studies on T-1249 were put on hold by Roche & Trimeris was that T-1249 was being cancelled because sales & profits from T-20 (Fuzeon) were inadequate because the drug was a self-injectable and therefore not well received by patients and doctors. This was the first question I asked Roche officials in interviews with the company about the news. Roche denied this was the reason and insisted that T-1249 formulation was the problem and just the opposite was true, that they were increasing their commitment to development of fusion inhibitors with a new agreement & infusion of capital into this project. The balance of the interview follows.
However, in an interview with a Roche official today, Roche says it is increasing it's commitment to Fuzeon and to discovering next generation fusion inhibitors and T- 1249 remains a candidate, says David Reddy, HIV Global Franchise leader for Roche. "Roche is not pulling back" says Reddy, who has been working in HIV for 20 years; there are plans to try to improve delivery of Fuzeon, "we strongly believe in Fuzeon, you can't escape its efficacy and we expect Fuzeon to take its rightful place in the standard of care for HIV therapy, we firmly believe in making Fuzeon a standard of care". You can't argue with the efficacy data which shows 2-fold improvement in achieving 1 log viral load reduction or <400 copies/ml with Fuzeon, says Reddy.
Although sales for Fuzeon have been disappointing since the product launch, Roche is increasing its commitment to Fuzeon, as well as to developing next generation fusion inhibitors. Fuzeon is administered twice daily by self administered subcutaneous injection and this has limited its appeal to patients. Because of limited manufacturing capacity upon launch of Fuzeon the commitment to Fuzeon had som limitations. But increased manufacturing capacity allows for expanded commitment to Fuzeon. Plans for expanded Fuzeon commitment in 2004 is discussed below. This commitment will address the limiations of Fuzeon administration.
Roche and Trimeris announced yesterday that they reached an agreement to focus on development of next generation peptides (fusion inhibitors) and to research improved delivery techniques. Roche researchers in Germany and Palo Alto will be focusing efforts on this in addition to researchers at Trimeris.
To improve Fuzeon usefulness and convenience of use, a preliminary pilot of once a day Fuzeon study has been conducted looking at short term pharmacokinetics and pharmacodynamics study of once daily versus twice daily administration of Fuzeon. This study compared the same daily dose of the current 90 mg bid dose of Fuzeon to using Fuzeon 180 mg once daily. The study has been completed and results will be reported in early 2004, about mid year. Additional studies are planned. Reddy of Roche says results will allow further studies but lets be cautious about over interpreting early results until we conduct larger studies. A once daily regimen could improve adherence and willingness to use Fuzeon.
As part of the Roche-Trimeris agreement, researchers at both companies will be trying to discover next generation peptides (fusion inhibitors). As well they will try to discover improved techniques for better delivery of the drug. They will research ways to administer these next generation drugs once daily, once a week, and perhpaps once a month. Several potential approaches will be researched.
One approach is to look for ways to attach Fuzeon to proteins or immunoglobulins to extend the half-life; to discover and utilize proteins and immunoglobulins that themselves have long half-lifes. Albumin is an example of a protein that could be attached to a new molecule (drug candidate) that could extend the drug half-life and thus reduce the time between administrations of the drug. Additional proteins or immunoglobulins could be utilized in this way.
Another approach is to discover new molecules (peptides, fusion inhibitors, drug candidates) that intrinsically will have longer half-lifes and therefore can be administerd less frequently. Straight chemical modification of a molecule or peptide or selection of peptide that itself has longer half-life is an approach.
Another approach they will be researching is to enhance the half-life of a drug by using a formulation technology. Examples of this are the enteric coated formulationof ddI. Another approach to extend drug half-life and reduce frequency of drug administration is to consider the method of drug boosting, as is done by boosting drug levels of one protease inhibitor by ritonavir.
Pegylation is a way to enhance and extend release of adrug. This technique has been used successfully with interferon for hepatitis C treatment. Pegylation has been looked at but does not give them enough. Other approaches appear more promising but pegylation has not been abandoned.
Discovering or developing a molecule with a longer half-life and coupling it with an extended release technique or a formulation technique that extends hail-life is another approach to finding a new and more effective way to deliver a fusion inhibitor with potency and less refquent adminstration. Reddy says some progress has been made in this area. Again, once a week or monthly administration has been suggested as a possibility.
Reddy says overall resources are being substantially increased for research collaboration to look for next generation peptides and delivery and increase is substantial. Overall, the number of researchers dedicated to this will be increased. As part of agreement between Roche and Trimeris the number of researchers will be increased, support level will be increased. Employee cutbacks may occur in other areas such as administrative or in clinical development. Trimeris has realligned workforce to focus on research.
New plans for Fuzon in 2004 are being implemented. On the Fuzeon supply front, Reddy says manufacturing capacity for Fuzeon is ahead of where it was expected to be, plans are to increase capacity at there plant in Colorado; we feel secure on the supply front. Since manufacturing and supply will be improved, Fuzeon marketing campaign and education programs will be intensified. There will be educational and marketing campaign directed towards clinicians, patients, and community-based organizations. There are plans for educational programs for AIDS service organiztions and patients directed to help in support of ways to improve use and understanding of Fuzeon.
Roche and Trineris are planning to launch nursing support programs to facilitate easier administration of Fuzeon and to provide additional support once treatment has started. The first program is for patients intiating therapy and offers virtually full time support and including a hotline where a nurse can be called to advise about drug preperation and administration, and to provide guidance for management of Fuzeon and care issues. A nationwide team of specially trained nurses on preperation and adminstration of Fuzeon will be provided. They will travel to doctor offices and to patient homes. This will be free of charge, starting 2004.
Up until now Fuzeon has been distributed through a single provider because of manufacturing and supply limits, so they could track patient use to make sure patients had continuous supply of drug. With improved supply distribution will expand to a more normal distribution using speciality distributors. This is expected to increase access and convenience for doctors and patients.
In recent years drug pricing and access drugs in developing nations has received much attention and Reddy was asked about the impact of these concerns. The HIV and drug environment is changing due to price and profit pressure. Reddy said, with regards to HIV Roche has recognized international issues and has adjusted its policy. We have had to change pricing and patent policy for HIV drugs and this is right thing to do to accomodate international access and to help price pressure in developing countries. Reddy went on to say that in the Western world HIV pharma is a business and a high risk endeavor. We must derive the profits that allow us to accept risk and accept failures that occur. And to generate profit and return investment for shareholders. This is important in each disease area including HIV. There are more complexities in HIV than in other diseases and Roche and other companies have worked through this. We've devised ways to innovate and continue in these areas. We expect that innovations will be rewarded. As examples Reddy described an HIV program failure and costs associated with Fuzeon development. Roche conducted research into developing an HIV TAT antagonist which was a failure because effectiveness was not found. The Fuzeon program cost has been upwards of 800 million Swiss francs (600+ million US) for research and development for Roche and Trimeris to develop Fuzeon and this number does not include phase III/IV marketing and promotion, surveillance studies, manufacturing expansion. This were bare costs for manufacturing and 500 person years of clinical activity.
Here is news coverage from several sources on the T-1249 announcement yesterday.
The Raleigh News and Observer January 6, 2004
Prompted by lackluster sales of its AIDS drug Fuzeon, Trimeris is halting development of a second-generation version of the drug and cutting 30 jobs, about one-quarter of the Durhamcompany's work force.
To reduce expenses, Trimeris is retooling its research and development programs. All of the employees who were let go Monday worked on the experimental AIDS treatment known asT-1249, said spokeswoman Robin Fastenau.
Halting studies on T-1249 puts more pressure on Trimeris to convince doctors and patients to use Fuzeon, a $20,000-a-year drug that is the money-losing company's only product on themarket.
"It's not good news," said Dr. David Boucher, an analyst with CE Unterberg Tobin in Denver. "But it's not make-or-break news."
Much anticipated when it won U.S. regulatory approval in March and hit the market soon after, Fuzeon has disappointed investors and industry analysts, who had projected about twice thedemand the drug has generated.
The weak demand for Fuzeon can be blamed on the method of administration and its high price. The drug must be injected in a patient's abdomen twice a day, -- other AIDS drugs are pills--and it costs about $20,000 for an annual supply, twice as much as other AIDS drugs.
As a result of weaker-than-expected sales, Trimeris shares have lost nearly two-thirds of their value in the past six months, dropping from a 52-week-high of $54.57 on July 15 to $20.24 atthe close of trading Monday.
Industry analysts projected the stock to fall today.
The cost-cutting measures will prolong Trimeris' cash reserves by reducing operational costs from $6 million to $7 million per month in 2003 to about $4 million per month this year, saidBob Bonczek, the company's chief financial officer.
Swiss pharmaceutical giant Roche, which manufactures and markets Fuzeon, plans to step up promotional efforts this year to boost sales, said Dr. David Reddy of Roche. Also, Trimeris andRoche are expanding research and development efforts to reduce the number of times Fuzeon must be injected to once a week or even once a month.
"We have several technologies we're trying to marry" with Fuzeon and other experimental drugs in the same group, said Dani Bolognesi, co-founder and chief executive officer of Trimeris.
Known as fusion inhibitors, the drugs prevent the virus that causes AIDS from entering and infecting a cell. T-1249, also an injectable, was the second fusion inhibitor Trimeris wasdeveloping. The companies said they may resume work on T-1249 later.
ZURICH (Reuters) - Roche's top HIV executive said on Tuesday theSwiss firm was several years away from launching a new type ofHIV treatment after it put on hold trials for an experimentaldrug developed with U.S. firm Trimeris .
T-1249, the drug whose clinical trials were halted, and HIV/AIDSdrug Fuzeon belong to a new class of drugs, known as fusioninhibitors, which are far more complex and costly to make thanconventional treatments.
"We see the opportunity with the fusion inhibitors to make whatreally is a quantum leap in terms of delivery -- of moving towardweekly administration as a target," said David Reddy, HIV globalfranchise leader for Roche .
"This isn't just months, we are talking years in terms of thestrategy we are taking," he added in a telephone interview withReuters.
Roche and Trimeris have already brought Fuzeon to the market.Despite initially disappointing sales, Roche expects Fuzeon togenerate peak annual sales of 500 million francs ($405 million)to 1.0 billion Swiss francs.
While T-1249 remained a potential candidate, Roche was looking atother molecules that have shown greater potency and could beeasier to administer, Reddy said.
Investors had expected T-1249 to be more potent and easier toadminister than Fuzeon. But Reddy denied that Roche may nowstruggle to maintain momentum in its HIV business.
He said the priority was to overcome initial concerns onadministering Fuzeon, which must be injected twice daily.
"This is very much where we are focused now, we firmly believe inits place in therapy -- driven by the unprecedented clinicalresults we have seen," Reddy said.
He said Roche was working on the life cycle management of theproduct as well as the development of the next generation ofmolecules, of which T-1249 remained a candidate.
Fuzeon requires 106 chemical steps to manufacture, 10 times morethan is needed to make a typical drug.
"We now have no issues with the manufacturing of (Fuzeon)," Reddysaid, adding plans were in place for expansion.
"It is fair to tell you we are on track with manufacturing or infact slightly ahead of plan," he added.
Trimeris, Roche halt trials of T-1249 HIV fusion inhibitor
By Ransdell Pierson and Bill Berkrot
NEW YORK (Reuters) - Swiss drugmaker Roche Holding AG and Trimeris Inc. on Monday said they had halted clinical trials of their experimental HIV fusion inhibitor, T-1249.
Trimeris, which developed the similar drug Fuzeon (formerly T-20) with Roche that was approved by U.S. regulators in March, has no other product currently in clinical trials.
Roche and Durham, North Carolina-based Trimeris said they had stopped trials of T-1249 because of shortcomings found in its formulation, which the partners did not describe.
T-1249 was expected to overcome some of the resistance and application problems of Fuzeon. Trimeris Chief Executive Dani Bolognesi said in a conference call that T-1249 was not dead, but that the company was "putting the current clinical program on hold until we arrive at a formulation that meets our objectives."
U.S. regulators had agreed to review the injectable medicine, which has been in phase I/II trials, on a "fast-track" basis once later trials were completed. The companies said they remain committed to fusion inhibitor development and signed an agreement to continue their partnership in research on drugs in this class.
The annual cost of Fuzeon is about $20,000 per patient, but Roche and Trimeris have said the cost is justified because dozens of steps are required to produce the injectable drug.
U.S. sales of Fuzeon reached only $10.7 million in the third quarter of 2003, partly because of the unwillingness of insurers to pay for it. The companies on Monday said they would undertake a number of initiatives designed to boost Fuzeon sales and were working on ways to reduce the number of injections necessary for patients.
Bolognesi said Trimeris planned to spend between $22 million and $27 million on research and development in 2004. He added that the company had sufficient cash to fund operations for at least the next two years.
"If sales of Fuzeon improve, the two years cash situation obviously resolves itself," he added.
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